Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics

The HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant native-like soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length unmodified Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV+ individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of full-length and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated full-length and soluble SOSIP HIV-1 Env trimers as immunogens.

HIV-1包膜糖蛋白（envelope glycoprotein, Env）三聚体位于病毒表面，是广谱中和抗体（broadly neutralizing antibodies, bNAbs）的作用靶点。重组天然样可溶性Env三聚体模拟物（如SOSIP三聚体）在旨在诱导广谱中和抗体的HIV-1疫苗研究中占据核心地位。为此，我们针对源自产生广谱中和抗体的HIV感染者早期Env序列（AMC011）的两类三聚体开展了直接且全面的比较：一类是包含跨膜结构域与胞质尾的全长未修饰Env三聚体，另一类是与其序列匹配的可溶性SOSIP三聚体。
结合广谱中和抗体PGT145或PGT151的全长AMC011三聚体，其结构与SOSIP三聚体的结构高度相似。抗原特性方面，全长三聚体与SOSIP三聚体表现相近，但与全长三聚体不同的是，SOSIP三聚体完全无法结合非中和抗体，这极有可能是SOSIP三聚体固有稳定化作用导致的结果。
此外，全长三聚体与SOSIP三聚体的糖基组成整体相似，但SOSIP三聚体的复合糖链更少、加工程度更低，这可能与其固有稳定化特性以及缺乏膜锚定有关。
本研究结果为如何最优使用并优化膜结合型全长Env三聚体与可溶性SOSIP HIV-1 Env三聚体作为免疫原提供了理论参考。